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  • br Conclusions In conclusion HIF signalling


    Conclusions In conclusion, HIF-1 signalling plays a key role in the response to cardiovascular diseases, from a metabolic and angiogenic point of view. This evokes HIF-1α as a potential therapeutic target in these diseases, and the recent advances in the development of PHD inhibitors are hopeful in this regard. However, there is still some concern that systemic treatment with hypoxia-mimetic drugs may lead to undesirable effects in healthy tissue, and it is important to note that HIF effects are tissue-specific. For instance, the Vadadustat trial reported several systemic side effects, as well as three deaths, in the treatment arm [176]. In the Roxadustat trial, five patients withdrew due to worsening side effects [174]. Despite being conserved targets for hypoxic Fluxametamide in a number of organs, the regulation of many targets via HIF-1 activation is achieved via different organ-specific mechanisms. Whether sustained HIF-1α upregulation is beneficial or deleterious for the heart is still under debate, and further investigation is needed to better understand the complex mechanisms at play. It may be that there is a cut-off point after which HIF signalling becomes detrimental to cardiac function [179,180]. Additionally, alternative hypoxic signalling mechanisms other than HIF, such as AMPK activation, may also provide a suitable alternative therapeutic target in cardiovascular diseases. HIF-targeting compounds developed so far have been designed with the kidney as their primary target. The current challenge is therefore the development of tissue-specific and PHD-selective inhibitors, which have so far been slow emerging. And although we have alluded to the potential of repurposing of compounds for use in cardiovascular diseases, this will have to be done on a compound-specific basis, with careful assessment of individual compounds.
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    Introduction Tissue hypoxia is a key feature of many pathologies, including cardiovascular disease, respiratory diseases and many cancers [1], and is also experienced by healthy individuals at high altitude. The physiological response to hypoxia includes changes that improve convective oxygen delivery [2], however it is increasingly recognised that changes in oxygen utilisation at the tissue level can also occur. A fall in the capacity for oxidative metabolism, including fatty acid oxidation, occurs in the skeletal muscle of humans and rodents following prolonged exposure to hypoxia [3]. A purported key player in regulating this response is peroxisome proliferator-activated receptor α (PPARα), a transcriptional regulator of fatty acid metabolism in heart, liver and skeletal muscle [4]. PPARα is downregulated in hypoxic cells under the action of hypoxia-inducible factor 1 (HIF1) [5], whilst its expression falls in lowlander muscle following acclimatisation to high altitude [6]. Meanwhile, in hypoxic rodent heart, the transcriptional response to hypoxia includes downregulation of PPARα target genes, and a switch in substrate preference away from fatty acid oxidation [[7], [8], [9], [10]]. Such changes in oxidative metabolism may occur alongside an increased reliance on glucose metabolism, including increased glycolysis [[11], [12], [13]], potentially improving the efficiency of oxygen utilisation (ATP produced per O2 consumed) and thereby matching tissue oxygen demand to the diminished supply, but this may also limit the capacity for ATP synthesis. In hypoxic rats, metabolic changes were associated with lower ATP levels in skeletal muscle, in comparison with normoxic rats [14]. These changes, however, were prevented in rats that received a moderate dose of sodium nitrate via the drinking water, protecting muscle ATP levels [14]. Inorganic nitrate (NO3−) can be consumed by humans as part of a normal, healthy diet with high levels present in green leafy vegetables and beetroot [15]. At a whole body level, nitrate supplementation has been shown to decrease the O2 cost of exercise in healthy subjects in both normoxic and hypoxic conditions [[16], [17], [18], [19], [20]], in a clinical population suffering from hypoxia as a result of chronic obstructive pulmonary disease [21], and also in subjects with decreased O2 carrying capacity due to blood donation [22].